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ORIGINAL CONTRIBUTION

Ischemic Stroke and Transient Ischemic Attackin Young Adults

Risk Factors, Diagnostic Yield, Neuroimaging, and Thrombolysis

Ruijun Ji, MD, PhD; Lee H. Schwamm, MD; Muhammad A. Pervez, MD; Aneesh B. Singhal, MD

Background: Approximately 10% to 14% of ischemicstrokes occur in young adults.

Objective: To investigate the yield of diagnostic tests,neuroimaging findings, and treatment of ischemic strokesin young adults.

Design: We retrospectively reviewed data from our Getwith the Guidelines–Stroke database from 2005 through2010.

Setting: University hospital tertiary stroke center.

Patients: A total of 215 consecutive inpatients aged 18to 45 years with ischemic stroke/transient ischemic attack.The mean (SD) age was 37.5 (7) years; 51% were male.

Results: There were high incidence rates of hyperten-sion (20%), diabetes mellitus (11%), dyslipidemia (38%),and smoking (34%). Relevant abnormalities were shownon cerebral angiography in 136 of 203 patients, on car-diac ultrasonography in 100 of 195, on Holter monitor-ing in 2 of 192; and on hypercoagulable panel in 30 of189 patients. Multiple infarcts were observed in 31% andwere more prevalent in individuals younger than age 35

years. Relevant arterial lesions were frequently detectedin the middle cerebral artery (23%), internal carotid ar-tery (13%), and vertebrobasilar arteries (13%). Cardio-embolic stroke occurred in 47% (including 17% with iso-lated patent foramen ovale), and 11% had undeterminedstroke etiology. The median National Institutes of HealthStroke Scale score was 3 (interquartile range, 0-9) and81% had good outcome at hospital discharge. Of the 29patients receiving thrombolysis (median National Insti-tutes of Health Stroke Scale score, 14; interquartile range,9-17), 55% had good outcome at hospital discharge andnone developed symptomatic brain hemorrhage.

Conclusions: This study shows the contemporary pro-file of ischemic stroke in young adults admitted to a ter-tiary stroke center. Stroke etiology can be determined innearly 90% of patients with modern diagnostic tests. Thecauses are heterogeneous; however, young adults havea high rate of traditional vascular risk factors. Throm-bolysis appears safe and short-term outcomes are favor-able.

Arch Neurol. Published online October 29, 2012.doi:10.1001/jamaneurol.2013.575

A PPROXIMATELY 10% TO 14%of ischemic strokes occur inadults ages 18 to 45 years.1-7

Stroke etiology in thispopulation differs by geo-

graphic region and has greater heteroge-neity than in older individuals.5,8,9 Evenwithin this population, the etiologic spec-trum varies according to study type (hos-pital based1-3 vs epidemiologic10), the ex-tent and availability of diagnostic evaluation,or the criteria used to ascribe etiology. Toour knowledge, data concerning ischemicstroke in young adults in the United Statesis limited to a few studies published morethan a decade ago.2-5 Advances in stroke di-agnostic tests, particularly neuroimaging, re-finement in classification schema,11 and the

advent of thrombolysis and stroke unit care,may have significantly impacted the pro-file of ischemic stroke in young adults. Westudied the diagnosis, management, andoutcome of ischemic stroke in young adultsadmitted to our comprehensive stroke cen-ter. A major objective was to determine theyield of diagnostic tests and characterizebrain and vascular imaging findings, which,to our knowledge, has not been the focusof prior studies.

METHODS

This retrospective study was approved by ourhospital’s human research committee. We re-viewed our American Heart Association Get

Author AffilDepartmentMassachusetHospital, Bo(Drs Ji, SchwSinghal); andNeurology, CUniversity, B(Dr Ji).

Author Affiliations:Department of Neurology,Massachusetts GeneralHospital, Boston, Massachusetts(Drs Ji, Schwamm, Pervez, andSinghal); and Department ofNeurology, Capital MedicalUniversity, Beijing, China(Dr Ji).

ARCH NEUROL PUBLISHED ONLINE OCTOBER 29, 2012 WWW.ARCHNEUROL.COME1

©2012 American Medical Association. All rights reserved.

Downloaded From: http://archneur.jamanetwork.com/ by a World Health Organization User on 11/29/2012

with the Guidelines–Stroke database12 from 2005 through 2010(n=2643 cases) to identify 215 consecutive patients ages 18 to45 years admitted with ischemic stroke or transient ischemicattack (TIA). Ischemic stroke was defined as a sudden focal neu-rologic deficit with imaging-confirmed infarct, and TIA as a tran-sient focal neurologic deficit without stroke on brain imaging.We excluded patients with stroke from cerebral sinovenousthrombosis, subarachnoid hemorrhage, or interventions.

Medical records and brain scans were reviewed by a strokeneurologist (R.J.), with supervision (A.B.S.). We extracted dataon patient demographics, relevant medical history (Table 1),National Institutes of Health Stroke Scale (NIHSS) score at ad-mission (obtained prospectively as per our clinical stroke pro-tocol), diagnostic test results, in-hospital treatment, and themodified Rankin Scale (mRS) score at hospital discharge. A fa-vorable outcome was defined as a mRS score of 0 to 2 at hos-pital discharge.

The results of relevant blood tests were categorized as nor-mal or abnormal based on our laboratory’s reference ranges(Table 2). Cerebrospinal fluid examination results were posi-tive if the white blood cell count was 5/µL or greater (to con-vert to �109 per liter, multiply by 0.001) or the protein levelwas greater than 0.06 g/dL (to convert to grams per liter, mul-tiply by 10.0). Transthoracic and transesophageal echocardi-ography reports were reviewed for cardioembolic sources, asdescribed previously.11 Electrocardiography and Holter moni-toring were considered positive if they showed atrial fibrillation/flutter. Lower-extremity Doppler ultrasonography and pelvicmagnetic resonance venography were considered positive if deepvein thrombosis was documented.

We reviewed diffusion-weighted imaging and fluid-attenuated inversion recovery sequences for lesion topogra-phy. If magnetic resonance imaging was not performed, com-puted tomography was reviewed. The presence, number,location, laterality, and arterial territory of ischemic lesions werenoted. Transfemoral, computed tomographic, and magnetic reso-nance angiography were reviewed for the presence of occlu-sion or stenosis in the culprit artery.

Stroke subtyping11 was based on information available at hos-pital discharge. Special consideration was given to patent fo-

ramen ovale (PFO) because of its controversial role in strokeand high detection rate in young stroke patients. Accordingly,PFO-associated strokes were subclassified as PFO with atrialseptal aneurysm (ASA), PFO Plus (ie, PFO and predisposingrisk for venous clot formation [eg, recent airline travel]), andisolated PFO.

SPSS version 16.0 for windows was used for statistical analy-sis. �2, Fisher exact, and t tests were used as appropriate. P � .05was considered statistically significant.

RESULTS

DEMOGRAPHICS AND RISK FACTORS

Of 215 patients, 203 (94%) had ischemic stroke and 12(6%) had TIA. The mean (SD) age was 37.5 (7) years,with a nearly equal distribution of men and women inthe full cohort and in the 2 age groups. Most patients werewhite, as expected for our referral base in the NortheastUnited States. Hypertension (20%), diabetes mellitus(11%), dyslipidemia (38%), and smoking (34%) werecommon (Table 1). There were high frequency rates ofprior headache (14%), illicit drug use (12%), and oralcontraceptive use (9%). Hypertension and diabetes melli-tus were more common in the 36-year-old to 45-year-old age group, and illicit drug use more common in the18-year-old to 35-year-old age group. Men had a higherfrequency of dyslipidemia, while women had a higher fre-quency of prior headaches. Three patients had postpar-tum stroke, and 2 had cancer-associated strokes.

DIAGNOSTIC TESTS

Most of the patients underwent extensive blood tests,Holter monitoring, and echocardiography (Table 2,Figure). Cerebrospinal fluid examination and toxicol-

Table 1. Baseline Characteristics

No. (%)

P Value

No. (%)

P ValueAll

(n = 215)Male

(n = 109)Female

(n = 106)18-35 y(n = 71)

36-45 y(n = 144)

DemographicsAge, mean (SD), y 37.5 (7) 38.5 (7) 36.4 (7) .03 29.2 (5) 41.5 (3)Sex 109 (51) 106 (49) 33 male/38 female 76 male/68 female .39White 174 (81) 83 (76) 91 (86) .07 63 (89) 111 (77) .04

Medical historyHypertension 42 (20) 26 (24) 16 (15) .11 6 (9) 36 (25) .004Diabetes mellitus 23 (11) 15 (14) 8 (8) .14 3 (4) 20 (14) .03Dyslipidemia 81 (38) 59 (54) 22 (21) �.01 26 (37) 55 (38) .82Valvular heart disease 10 (5) 5 (5) 5 (5) �.99 3 (4) 7 (5) �.99CAD 7 (3) 4 (4) 3 (3) �.99 0 (0) 7 (5) .10Cardiomyopathy 7 (3) 4 (4) 3 (3) �.99 3 (4) 4 (3) .69Atrial fibrillation 3 (1) 1 (1) 2 (2) .62 1 (1) 2 (1) �.99CHF 2 (1) 1 (1) 1 (1) �.99 0 (0) 2 (1) �.99Prior headaches 31 (14) 8 (7) 23 (22) .003 10 (14) 21 (15) .92Cigarette smoking 73 (34) 37 (34) 36 (34) .99 28 (39) 45 (31) .23Illicit drug use 26 (12) 13 (12) 13 (12) .94 13 (18) 13 (9) .05OCP use 20 (9) 20 (19) 12 (17) 8 (6) .02Recent pregnancy 3 (1) 3 (3) 1 (1) 2 (1) �.99Cancer 2 (1) 1 (1) 1 (1) �.99 1 (1) 1 (1) .55

Abbreviations: CAD, coronary artery disease; CHF, congestive heart failure; OCP, oral contraceptive pill.




ogy screening were performed when clinically indi-cated. The diagnostic yield was relatively low for Holtermonitoring (1%), toxicology screening (5%), and vas-culitis panel (�5%), as well as relatively high for echo-cardiography (51%) and angiography (64%). Lipid panelresult abnormalities were significantly more common inmen. Cerebrospinal fluid examination results were ab-normal in 5 of 34 patients (15%).

Hypercoagulable panel screening results were posi-tive in 16% of patients, including 3% with hereditary pro-thrombin gene or factor V Leiden mutations and 13% withlow protein C, protein S, or antithrombin III levels. Themost common abnormality was a low protein S level,mostly in women (18% vs 5%; P = .004), including 6women taking oral contraceptives. Eight patients had per-sistently low levels on follow-up testing.

Table 2. Diagnostic Test Results

Diagnostic TestYield,

No./No.

No. (%)

P Value

No. (%)

P ValueMale Female 18-35 y 36-45 y

BloodHypercoagulable panel 30/189 10 (11) 20 (21) .05 12 (21) 18 (14) .23

Functional protein C�70% 2/189 1 (1) 1 (1) �.99 1 (2) 1 (1) .52Functional protein S�70% 23/189 5 (5) 18 (18) .004 9 (16) 14 (11) .35Functional antithrombin III�80% 3/189 1 (1) 2 (2) �.99 1 (2) 2 (2) �.99Factor V Leiden mutation 4/189 3 (3) 1 (1) .37 2 (3) 2 (2) .59Prothrombin 20210 mutation 1/189 0 (0) 1 (1) �.99 0 (0) 1 (1) �.99

Lipid panelTotal cholesterol �200 mg/dL 34/205 25 (24) 9 (9) .004 11 (17) 23 (17) .93LDL cholesterol �130 mg/dL 28/205 21 (20) 7 (7) .006 10 (15) 18 (13) .75HDL cholesterol �35 mg/dL 43/205 34 (33) 9 (9) �.01 12 (18) 31 (22) .58Lipoprotein (a)�3 mg/dL 22/174 14 (16) 8 (9) .17 5 (9) 17 (14) .39

Hemoglobin A1c �6.4% 31/167 20 (23) 11 (14) .17 7 (14) 24 (21) .32Homocysteine �1.62 mg/L 14/184 11 (12) 3 (3) .03 5 (9) 9 (7) .69High-sensitive CRP�1.2 mg/L 22/203 9 (9) 13 (13) .38 5 (7) 17 (13) .22Anticardiolipin IgG�15 GPL 11/207 6 (6) 5 (5) .77 4 (6) 7 (5) .74Anticardiolipin IgM�15 MPL 18/207 3 (3) 15 (15) .003 5 (8) 13 (9) .73Antinuclear antibody 3/86 2 (6) 1 (2) .59 2 (6) 1 (2) .57Lupus antibody 1/8 0 (0) 1 (50) .25 0 (0) 1 (33) .38Serum/urine toxicology 7/136 2 (3) 5 (8) .25 4 (8) 3 (4) .43

CSF examination 5/34 4 (27) 1 (5) .15 3 (17) 2 (13) �.99Holter monitoring 2/192 1 (1) 1 (1) �.99 1 (2) 1 (1) .54Echocardiography, TTE/TEE

Vegetation or mass 4/195 3 (3) 1 (1) .62 3 (5) 1 (1) .11PFO 96/195 37 (37) 59 (62) .001 37 (57) 59 (45) .16

PFO with ASA 13/96 8 (22) 5 (8) .12 5 (14) 8 (14) �.99Isolated PFO 83/96 29 (78) 54 (92) .12 32 (86) 51 (86) �.99

Abbreviations: ASA, atrial septal aneurysm; CRP, C-reactive protein; CSF, cerebrospinal fluid; PFO, patent foramen ovale; TEE, transesophagealechocardiography; TTE, transthoracic echocardiography.

Conversion factors: To convert cholesterol to millimoles per liter, multiply by 0.0259; CRP to nanomoles per liter, multiply by 9.524; hemoglobin A1c toproportion of total hemoglobin, multiply by 0.01; and homocysteine to micromoles per liter, multiply by 7.397.

0

100

40

50

60

70

80

90

Patie

nts,

%

30

20

10

HypercoagulationPanel

Serum/UrineToxicologyScreening

VasculitisPanel

CSFExamination

Echocardiography HolterMonitoring

CT or MRI Angiography

Figure. Diagnostic tests in young adults with ischemic stroke. The lighter bars show the percentage of patients who underwent a certain test and the black barsshow the percentage of tests showing a positive result relative to stroke etiology (ie, diagnostic yield). CSF indicates cerebrospinal fluid; CT, computedtomography; MRI, magnetic resonance imaging. See “Methods” section for individual tests included under each panel.




Contrast transthoracic echocardiography was per-formed in 91% of patients and transesophageal echocar-diography in 40%. A positive transthoracic echocardi-ography or transesophageal echocardiography result wasdocumented in 100 of 195 patients (51%). Ninety-six of100 patients with a positive echocardiography result hada PFO, including 13 with ASA and 83 without ASA. Pat-ent foramen ovale was implicated as a stroke etiology in76 patients and was considered incidental in cases withalternate causes such as carotid dissection.

ISCHEMIC LESION TOPOGRAPHY

Computed tomography was performed in 97% of pa-tients and magnetic resonance imaging in 98%; 203 pa-tients had brain infarctions. Single infarcts were ob-served in 69% (Table 3). Multiple infarcts were morecommon in the 18-year-old to 35-year-old age group (41%vs 25%; P = .03). Supratentorial infarcts were more com-mon in women (89% vs 67%; P � .01). Patients with su-pratentorial infarcts had significantly higher NIHSS scoresat admission compared with those with infratentorial in-farcts (median NIHSS score, 7 vs 3, respectively; P � .001).Of the affected arterial territories, 56% were middle ce-rebral, 3% were anterior cerebral, 7% were combinedmiddle and anterior cerebral, 8% were posterior cere-bral, 21% were vertebrobasilar, and 5% were multiple.

NEUROVASCULAR IMAGING

Transfemoral, computed tomographic, or magnetic reso-nance cerebral angiography was performed in 99% of pa-tients and 20% additionally underwent vascular ultraso-nography studies. Embolic occlusion, severe stenosis

(�70% by visual estimate), or underlying arteriopa-thies such as premature atherosclerosis (Table 4) or ce-rebral artery dissection or Moyamoya disease (Table 5)were observed in 64% of patients, including 42% withangiographic abnormalities in the anterior circulation ar-teries, 14% in the posterior circulation arteries, and 8%with diffuse abnormalities from conditions such as re-versible cerebral vasoconstriction syndrome. Proximalmiddle cerebral artery lesions were most common (23%),followed by lesions of the internal carotid artery and thevertebrobasilar system.

STROKE ETIOLOGY

The most common stroke subtype was cardioembolic(47%): 5% were PFO with ASA, 14% were PFO Plus, 17%were isolated PFO, and 11% had established cardioem-bolic sources (Table 4 and Table 5). Large-artery athero-sclerosis and small-vessel disease were relatively uncom-mon, and they occurred exclusively in patients older thanage 36 years. More than one-third of patients proved tohave other well-defined causes. Multiple etiologies werefound in 4 patients (2%). The etiology remained unde-termined in only 9%, including 18 patients with crypto-genic stroke despite a thorough workup and 1 patientwho died before testing was completed.

TREATMENT AND OUTCOME

Four patients underwent hemicraniectomy for malig-nant brain edema. At the time of hospital discharge, 87%of patients were taking antiplatelet agents or anticoagu-lants (5% were on both), and 32% were taking statins.The median NIHSS score at admission was 3 (interquar-

Table 3. Brain and Vascular Imaging

Lesion Location

No. (%)

P Value

No. (%)

P ValueAll

(n = 203)Male

(n = 103)Female

(n = 100)18-35 y(n = 69)

36-45 y(n = 134)

Supratentorial 158 (78) 69 (67) 89 (89) �.001 53 (77) 105 (78) .80Multiple 62 (31) 32 (31) 30 (30) .87 28 (41) 34 (25) .03Laterality

Left side 111 (55) 52 (51) 59 (59) .22 37 (54) 74 (55) .83Right side 77 (38) 43 (42) 34 (34) .26 26 (38) 51 (38) .96Midline, brainstem 15 (7) 8 (8) 7 (7) .83 6 (9) 9 (7) .61

Cerebral Angiography All(n = 212)

Male(n = 108)

Female(n = 104)

18-35 y(n = 69)

36-45 y(n = 143)

No significant abnormality 76 (36) 41(38) 35 (34) .57 16 (23) 60 (42) .008Internal carotid artery 27 (13) 13 (12) 14 (13) .83 8 (12) 19 (13) .73

Origin 20 (9) 10 (9) 10 (10) �.99 4 (6) 16 (11) .21Terminus, T lesion 7 (3) 3 (3) 4 (4) .72 4 (6) 3 (2) .22

Middle cerebral artery 59 (28) 25 (23) 34 (33) .12 24 (35) 35 (24) .12M1/M2 48 (23) 20 (19) 28 (27) .14 20 (29) 28 (20) .13M3/M4 11 (5) 5 (5) 6 (6) .71 4 (6) 7 (5) .75

Anterior cerebral artery 4 (2) 4 (4) 0 (0) .12 1 (1) 3 (2) �.99Posterior cerebral artery 9 (4) 3 (3) 6 (6) .33 4 (6) 5 (3) .48Basilar artery 5 (2) 3 (3) 2 (2) �.99 2 (3) 3 (2) .66Vertebral artery 8 (4) 7 (6) 1 (1) .07 2 (3) 6 (4) �.99PICA/AICA/SCA 7 (3) 5 (5) 2 (2) .45 5 (7) 2 (1) .04Multiple arteries 17 (8) 7 (6) 10 (10) .40 7 (10) 10 (7) .43

Abbreviations: AICA, anterior-inferior cerebellar artery; PICA, posterior-inferior cerebellar artery; SCA, superior-cerebellar artery.




tile range, 0-9). The mean (SD) length of stay was 6.2(6) days (range, 1-54 days). More than 80% of patients

had good clinical outcome (mRS score, 0-2). Poor out-come (mRS score, 5-6) was documented in 29 patients,including 7 who died (Table 4).

Thrombolysis was administered to 29 patients (13.5%),including 19 who received intravenous tissue plasmino-gen activator therapy alone, 6 who received intra-arterial thrombolysis, and 4 who received combined in-travenous/intra-arterial thrombolysis. Their median NIHSSscore at admission was 14 (interquartile range, 9-17) andmean (SD) length of stay was 7.1(5) days (range, 1-20days). Angiographic occlusion was documented in 93%.Sixteen patients (55%) had good outcome, and none de-veloped symptomatic intracerebral hemorrhage.

COMMENT

Our study shows the contemporary profile of ischemicstroke in young adults in a tertiary referral center in theNortheast United States. The age and sex distribution inour cohort is similar to that of other US-based studieswith a similar age range.2,3 However, studies with ahigher age cutoff have found a higher proportion ofmales.1 Similar to recent studies,1,7 there were high inci-dence rates (compared with young individuals withoutstroke13) of modifiable stroke risk factors such as dyslip-idemia, hypertension, diabetes mellitus, and smoking,which contribute to higher rates of recurrent vascularevents.14 Despite the relatively high incidences of modi-fiable risk factors, stroke etiology was attributed to large-artery atherosclerosis and small-vessel disease in lessthan 10%, suggesting that vascular risk factors increasethe susceptibility to stroke from other causes. These datare-emphasize the need to implement evidence-basedstroke prevention targeting traditional risk factors inyoung adults.1,7

Table 4. Stroke Subtypes, Treatments, and Outcomes

No. (%)

P Value

No. (%)

P ValueAll

(n = 215)Male

(n = 109)Female

(n = 106)18-35 y(n = 71)

36-45 y(n = 144)

SubtypeLarge-vessel atherosclerosis 4 (2) 1 (1) 3 (3) .37 0 (0) 4 (3) .31Small-vessel disease 14 (7) 9 (8) 5 (5) .29 0 (0) 14 (10) .006Cardioembolism 100 (47) 44 (40) 56 (53) .07 39 (55) 61 (42) .08Other determined etiology 74 (34) 39 (36) 35 (33) .67 24 (34) 50 (35) .89Multiple etiologies 4 (2) 2 (2) 2 (2) �.99 3 (4) 1 (1) .11Undetermined 18 (8) 14 (13) 4 (4) .02 4 (6) 14 (10) .31Incomplete evaluation 1 (1) 0 (0) 1 (1) .49 1 (1) 0 (0) .33

In-hospital treatmentAntiplatelet 133 (62) 61 (56) 72 (68) .07 46 (65) 87 (60) .53Anticoagulant 65 (30) 34 (31) 31 (29) .76 24 (34) 41 (29) .42Statins 68 (32) 39 (36) 29 (27) .24 22 (31) 46 (32) .77Intravenous thrombolysis 19 (11) 15 (14) 8 (8) .14 10 (14) 13 (9) .26Intra-arterial recanalization 10 (6) 7 (6) 5 (5) .59 3 (4) 9 (6) .76Hemicraniectomy 4 (2) 4 (4) 0 (0) .12 1 (1) 3 (2) �.99

Discharge mRS score0-2 174 (81) 85 (78) 89 (8) .26 62 (87) 112 (78) .093-4 12 (6) 6 (6) 6 (6) .96 2 (3) 10 (7) .355-6 29 (14) 18 (17) 11 (10) .19 7 (10) 22 (15) .27

Abbreviation: mRS, modified Rankin Scale.

Table 5. Cardioembolic and Other Determined Etiologies

No. (%)

Cardioembolic 100 (47)PFO associated 76 (35.3)

PFO with ASA 11 (5.1)PFO Plus 29 (13.5)Isolated PFO 36 (16.7)

Cardiomyopathy 10 (4.7)Valvular heart disease 7 (3.3)Fibroelastoma 3 (1.4)Infective endocarditis 1 (0.5)Myocardial infarction/left ventricular thrombus 2 (0.9)Ventricular septal aneurysm 1 (0.5)

Other determined 74 (34)Dissection 29 (13.5)

Carotid 20 (9.3)Vertebral/basilar 9 (4.2)

Reversible cerebral vasoconstriction syndromes 11 (5.1)Moyamoya disease 7 (3.3)Hypercoagulable state 6 (2.8)

Factor V Leiden mutation 3 (1.4)Protein S deficiency 2 (0.9)Antithrombin III deficiency 1 (0.45)

Primary angiitis of central nervous system 5 (2.3)Drug-induced stroke 5 (2.3)Migrainous infarction 3 (1.4)Antiphospholipid antibody syndrome 2 (0.9)Thrombosed aneurysm 2 (0.9)Hyperhomocysteinemia, 176 µmol/L, MTHFR

gene mutation1 (0.45)

Radiation arteriopathy 1 (0.45)Essential thrombocytosis 1 (0.45)Cancer 1 (0.45)

Abbreviations: ASA, atrial septal aneurysm; PFO, patent foramen ovale.




A novel feature is that 99% of patients were adjudi-cated as having a complete diagnostic workup. An ex-tensive battery of tests was routinely performed, whichmight explain why we found a relatively low rate of un-determined stroke etiology compared with other stud-ies.1,3,8 The use of a validated algorithm11,15 to classify eti-ology into standard TOAST (Trial of Org 10172 in AcuteStroke Treatment) subtypes lends confidence to our re-sults. Patent foramen ovale–associated strokes were con-sidered cardioembolic, as per TOAST criteria.16 Unlikeprior publications,17 we further classified PFO-associated strokes based on the presumed risk level (ie,PFO with ASA, PFO Plus, and isolated PFO). This sub-classification was justified by the high detection rate ofPFO in our study, the possible significance of transienthypercoagulable panel abnormalities in patients with PFO,and existing uncertainties about PFO treatment,17 as wellas the relationship between PFO and stroke. This levelof detail will allow reclassification of isolated PFO or PFOPlus from cardioembolic to undetermined, if the strokerisk attributable to PFO changes in the future.

Young adults with stroke typically undergo a wide spec-trum of diagnostic tests, but there is little knowledge aboutthe tests’ yield or cost-effectiveness. We found a low yieldfor inpatient Holter monitoring, serum/urine toxicol-ogy, and vasculitis panel tests. Hypercoagulable panel re-sults at admission were positive in 30 patients, 17 of whomhad transient hypercoagulable states; the rest had per-sistent abnormalities or inherited mutations. Conceiv-ably, transient reductions in the levels of these clottingcascade proteins elevate stroke risk, particularly in pa-tients with PFO, which further justifies the PFO Plus cat-egory used in our study. We note that the association be-tween thrombophilia and stroke remains controversial,and the consequences of treating young adults with an-ticoagulants based on such results needs to be carefullyconsidered.18 Cardiac ultrasonography was positive in 100patients (51%), including 96 with a PFO. The true diag-nostic yield of cardiac ultrasonography is probably muchlower because PFO was deemed incidental in patients withalternate etiologies and because the significance of anisolated PFO remains uncertain.19 Our data reflect thediagnostic yield of tests in a real world academic strokesetting. Further studies are warranted to determine cost-effectiveness and design appropriate stroke diagnostic al-gorithms in young adults.

The detailed analysis of brain and vascular imagingprovides insights into the pathophysiology of stroke inthis population. Single infarctions were more commonin the 36-year-old to 45-year-old age group, consistentwith the higher incidence of small-vessel disease and ath-erosclerosis in this age group. Both age groups showeda similar distribution of supratentorial vs infratentorialinfarcts. In contrast, Putaala et al1 found no significantdifference in the number of single infarcts between agegroups, and older individuals had a higher incidence ofanterior-circulation lesions. These differences may be ex-plained by the distinct populations and different agegroups being studied. We found a high yield of vascularimaging (substantially higher than in the general strokepopulation20,21 or thrombolysed patients22), and arte-riopathies are known to be the most common cause of

stroke in young individuals.23 These data justify routinecerebrovascular imaging in young adults with stroke-like symptoms.

In our study, nearly 15% of patients required con-stant nursing care or died before hospital discharge.Young stroke survivors are known to develop substan-tial emotional and socioeconomic issues,24 and morethan 10% develop recurrent vascular events within 5years.14 From the perspective of secondary prevention, itis reassuring that 92% of our patients received antiplate-let or anticoagulant therapy, or both, at hospital dis-charge. However, the ideal duration, safety, and efficacyof these medications in young stroke patients is notclear. Cholesterol-lowering medications were adminis-tered to only 32% of patients, possibly reflecting uncer-tainties in exposing young adults with nonatheroscle-rotic stroke to long-term statin therapy. A relativelylarge number received thrombolysis, and no patientdeveloped hemorrhagic complications; however, to ourknowledge, there is little data concerning the safety andefficacy of thrombolysis in young adults or those withrelatively uncommon stroke etiologies. Such knowledgegaps need to be addressed in prospective studies, andtreatment and prevention guidelines that specificallyaddress stroke in young adults need to be developed.

In conclusion, this study provides contemporary in-formation on risk factors, diagnostic tests, imaging, throm-bolysis, and secondary prevention of ischemic stroke inyoung adults. The clinical setting in a tertiary stroke cen-ter limits the generalizability of our results. Neverthe-less, our data may prove useful in developing cost-effective diagnostic strategies, understanding thepathophysiology, and refining the management of ische-mic stroke in young adults.

Accepted for Publication: May 16, 2012.Published Online: October 29, 2012. doi:10.1001/jamaneurol.2013.575Correspondence: Aneesh B. Singhal, MD, ACC-729C, De-partment of Neurology, Massachusetts General Hospi-tal, Boston, MA 02114 ([email protected]).Author Contributions: Study concept and design: Sing-hal. Acquisition of data: Ji, Schwamm, Pervez, and Sing-hal. Analysis and interpretation of data: Ji, Schwamm, Per-vez, and Singhal. Drafting of the manuscript: Ji, Pervez,and Singhal. Critical revision of the manuscript for impor-tant intellectual content: Ji, Schwamm, Pervez, and Sing-hal. Statistical analysis: Ji and Singhal. Administrative, tech-nical, and material support: Schwamm. Study supervision:Schwamm, Pervez, and Singhal.Conflict of Interest Disclosures: Dr Schwamm has servedas a consultant for the Massachusetts Department ofHealth and Lundbeck International Steering Commit-tee, and as an unpaid chair for the American Heart As-sociation’s Get with the Guidelines–Stroke program.Funding/Support: This study was funded by grantsR01NS051412 and R21NS077442 from the National In-stitutes of Health/National Institute of Neurological Dis-orders and Stroke; grant 30700240 from the National Na-ture Science Foundation of China; and grant 2008B30from the Nova Program, Beijing Science and Technol-ogy Commission.




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